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© 2000 American Society for Clinical Oncology Outcome Of CNS Disease At Diagnosis in Disseminated Small Noncleaved-Cell Lymphoma and B-Cell Leukemia: A Children’s Cancer Group StudyFrom the Memorial Sloan-Kettering Cancer Center and New York University Medical Center, New York, NY; Children’s Cancer Group Operations Center, Arcadia, CA; Lombardi Cancer Center, Washington, DC; and Children’s Hospital of Philadelphia, Philadelphia, PA. Address reprint requests to Sridharan Gururangan, MRCP(UK), Children’s Cancer Group, PO Box 60012, Arcadia, CA 91066-6012; email gururooz{at}mc.duke.edu
PURPOSE: To examine the impact of initial CNS involvement on outcome and patterns of failure in patients with disseminated small noncleaved-cell lymphoma and B-cell leukemia who were treated in four successive Children’s Cancer Group trials. PATIENTS AND METHODS: Of 462 patients with disseminated disease, 49 (10.6%) had CNS disease at diagnosis (CNS+). CNS disease included meningeal disease or CNS parenchymal masses with or without cranial neuropathies (CSF+/Mass; CNPs) in 36 patients and isolated CNPs in 13. Of the CNS+ patients, 28 had M2 (5% to 25% blasts) or M3 (> 25% blasts) bone marrow involvement. All patients received protocol-based systemic and intrathecal chemotherapy. Thirty-six patients also received CNS irradiation. RESULTS: Relapses occurred in 21 (43%) of 49 patients, predominantly in the CNS (71%) and bone marrow (52%). The 3-year event-free survival ± SE for all patients with CNS+ disease was 45% ± 7%. Patients with CSF+/Mass had a nominally higher treatment failure rate compared with patients with CNS- after adjusting for marrow status and lactate dehydrogenase (LDH) diagnosis, with a relative failure rate (RFR) of 1.52 (95% confidence interval [CI], 0.88 to 2.6; P = .15). In comparison, the RFRs for patients with M2 or M3 marrow and for those with LDH levels greater than 500 IU/L after adjusting for CNS disease were 1.4 (95% CI, 0.96 to 2.0; P = .029) and 2.2 (95% CI, 1.5 to 3.0; P < .001), respectively. The RFR for patients with isolated CNPs was 0.87 (95% CI, 0.36 to 2.1; P = .76). CONCLUSION: We conclude that, with the treatments used during the period covered by these studies, the presence of CSF+/Mass CNS disease at diagnosis was associated with a nominally worse outcome independent of initial bone marrow status and LDH level, but the effect was not statistically significant.
GREAT STRIDES HAVE been made in the treatment of localized small noncleaved-cell lymphoma (SNCCL) in children, with cure rates of greater than 85%.1,2 The prognosis for patients with disseminated disease, however, has not been optimal,3 although recent reports suggest that it may be steadily improving.4-9 Factors that traditionally have been thought to contribute to the poor outcome in patients with disseminated SNCCL include bone marrow involvement and CNS disease at diagnosis or relapse.10 Recent reports, however, have shown that, with intensive risk-adapted therapies, the prognosis for patients with disseminated disease and particularly those with CNS involvement has remarkably improved.8,9,11 It is possible that the poor prognosis associated with CNS involvement in previous studies may have been predominantly a result of the commonly coexistent bone marrow disease and the use of less intensive or less effective therapies. Therefore, to further characterize the impact of this variable, we analyzed the incidence, patterns of relapse, and outcome of CNS disease at diagnosis of patients with disseminated SNCCL who were treated on four Children’s Cancer Group (CCG) protocols between 1977 and 1995.12-15
Patient Characteristics The study population comprised patients with disseminated SNCCL treated on CCG protocols between 1977 and 1995. This period encompassed the following CCG studies: CCG-551 (1977 to 1982), CCG-503 (1983 to 1989), CCG-552 (1986 to 1989), and CCG-5911 (1991 to 1995). A total of 467 patients with disseminated disease were treated on these studies. Information on bone marrow status was not available on five patients, who were therefore excluded from the analysis. Of the remaining 462 patients, 49 satisfied the criteria for CNS disease.
Criteria for Disseminated Disease at Diagnosis
Criteria for CNS Disease at Diagnosis The criteria for CNS disease at diagnosis in all four studies included the presence of the following in isolation or combination: (1) unequivocal blasts in the CSF on cytospin examination, (2) cranial neuropathies (CNPs), and (3) intraparenchymal CNS masses as demonstrated by neuroradiologic studies.12,14 The presence of isolated CNPs was one of the listed criteria for CNS disease in the CCG-503, -552, and -5911 studies. Although isolated CNP was not one of the criteria for CNS disease in the CCG-551 study, we did find one patient on central review who presented with isolated multiple CNPs and who received CNS-directed therapy. This patient was included in the study. Three patients who presented with paraplegia resulting from extradural compression of the spinal cord without CSF or intraparenchymal involvement of the CNS were not considered to have CNS disease in this study and were excluded from the analysis.
Treatment CCG-551. This study12 randomized patients to receive induction therapy with either cyclophosphamide (CPM), vincristine (VCR), prednisone (PRED), and intravenous methotrexate (MTX) (COMP regimen) or CPM, VCR, PRED, and daunorubicin (DAUNO) (LSA2L2 regimen). Patients randomized to receive the COMP regimen received maintenance therapy with this regimen monthly for 18 months after induction. Patients on the LSA2L2 regimen received consolidation chemotherapy with cytarabine (Ara-C), thioguanine (6-TG), L-asparaginase, and carmustine followed by maintenance cycles of 6-TG + CPM, hydroxyurea + DAUNO, MTX + carmustine, and Ara-C + VCR for 18 months. In both treatment groups, CNS prophylaxis included intrathecal (IT) MTX twice during induction (all patients) and twice during consolidation (LSA2L2 patients only) and every 4 weeks (COMP regimen group) or twice during each cycle of maintenance therapy (LSA2L2 patients only). Patients with meningeal disease at diagnosis received an additional dose of IT MTX during induction therapy. Patients with CNS disease at diagnosis also received cranial irradiation (24 Gy) beginning with the initiation of induction therapy. CCG-503. In this study,13 patients were randomized to receive either the COMP regimen or the COMP + DAUNO regimen during induction and were continued with the same therapy during maintenance for a minimum of 15 cycles. Patients with CNS and bone marrow involvement nonrandomly received COMP + DAUNO. All patients received IT Ara-C on day 0 of induction therapy. Additional CNS prophylaxis included IT MTX on day 16 of induction and on day 0 of each cycle of maintenance chemotherapy. Patients with CNS disease at diagnosis received three additional doses of IT MTX and Ara-C during induction. They also received cranial irradiation (24 Gy for CNS parenchymal involvement and 15 Gy for meningeal disease) and spinal irradiation (8 Gy) immediately after diagnosis. CCG-552. The therapeutic regimen for this study began with an induction course of three cycles of CPM, DAUNO, VCR, methylprednisolone, and PRED (CHOP regimen). This was followed by a CNS consolidation phase with CHOP chemotherapy and more intensive IT therapy. The subsequent maintenance treatment lasted 36 to 45 weeks.14 This phase consisted of five blocks of therapy. Each block lasted 9 weeks and consisted of three cycles: cycle 1, Ara-C and 6-TG; cycle 2, MTX and etoposide; and cycle 3, CHOP chemotherapy. CNS prophylaxis was triple IT chemotherapy (MTX, Ara-C, and hydrocortisone [HC]) with seven weekly injections during induction therapy, five weekly doses during consolidation, and one injection during cycle 2 of each maintenance course. Patients with CNS disease at diagnosis received four additional doses of the triple IT chemotherapy during induction. They also received craniospinal irradiation (24 Gy to the cranium and 18 Gy to the spine) if the CSF WBC count was greater than 5 cells/mm3 with a positive cytospin. Patients with CNS parenchymal masses also received 10 Gy to the involved area. CCG-5911. This study was a randomized comparison of an Orange regimen versus a French regimen.14 The Orange regimen arm of the CCG-5911 study consisted of induction therapy with CHOP chemotherapy followed by a consolidation phase with ifosfamide and etoposide (VP-16).15 CNS intensification therapy with dexamethasone, Ara-C, VP-16, cisplatin, and L-asparaginase was then given. Maintenance therapy consisted of one (standard-risk patients) or two courses (high-risk patients), with three cycles per course: CHOP (cycle 1), ifosfamide + VP-16 (cycle 2), and the regimen of dexamethasone, Ara-C, VP-16, cisplatin, and L-asparaginase (cycle 3). The reduction phase of the French regimen arm of the CCG-5911 study consisted of CPM, VCR, and PRED. This was followed by twocourses of CPM, VCR, PRED, doxorubicin, and high-dose MTX with leucovorin rescue. Patients then received a consolidation phase with two courses of high-dose Ara-C and VP-16. Maintenance therapy consisted of one or two courses with two cycles per course of the following: CPM, VCR, PRED, doxorubicin, and high-dose MTX with leucovorin rescue (cycle 1) and high-dose Ara-C + VP-16 (cycle 2). CNS prophylaxis in the Orange regimen consisted of two doses of IT Ara-C and HC during the induction phase, two in the consolidation phase, and one during the intensification and maintenance phases. For patients with CNS disease at diagnosis, additional doses of IT Ara-C, MTX, and HC were given during the induction and consolidation phases of therapy. These patients also received cranial irradiation of 1,800 Gy at the beginning of the consolidation phase. CNS prophylaxis in the French regimen consisted of IT Ara-C at the beginning of induction, during consolidation, and during each cycle of maintenance therapy. For patients with CNS disease at diagnosis, four doses of IT Ara-C and HC and two doses of IT Ara-C, MTX, and HC were given during the induction phase. In addition, three doses of IT Ara-C, MTX, and HC were administered during the consolidation and maintenance phases. Cranial irradiation of 1,800 Gy was given to patients with CNS disease at diagnosis during the first cycle of maintenance therapy.
Statistical Methods
Clinical Characteristics of Patients With CNS Disease The age and sex distributions for the 462 patients in the cohort are listed in Table 1. There is no difference in these characteristics between patients with and those without CNS disease. All patients with CNS disease had multiple sites of involvement. Primary sites of involvement included the head and neck region (nasopharynx, sinuses, base of skull, cervical lymph nodes, and jaw) in 24 patients, abdomen (liver, spleen, kidneys, lymph nodes, and caecum) in 32 patients, and other sites (bone, pleura, mediastinum, and testes) in 16 patients.
Types of CNS Disease
Bone Marrow Status and Serum LDH Level at Diagnosis
Serum LDH levels were available in 356 patients without CNS disease and in 42 patients with CNS disease. The median LDH values at diagnosis were 586 and 742 IU/L, respectively, with 30% and 45% of LDH values exceeding 1,000 IU/L in each group, respectively (Table 1).
CNS Irradiation
Adverse Events
Disease progression versus bone marrow status. In the group with isolated CNPs, two of seven patients with M1 marrow and four of six patients with M2 or M3 marrow suffered disease progression. In the group with CSF+/Mass, four of 14 patients with M1, compared with 11 of 22 patients with M2 or M3 status, had relapse of disease.
Disease progression versus LDH level at diagnosis.
In the group with isolated CNPs, two of four patients with LDH levels of Other adverse events. Seven patients, all CNS+, died of causes not related to disease progression (Table 3): five died of toxicity related to tumor lysis or infection and two died of secondary malignancy, one of these two of glioblastoma multiforme 7 years after cranial irradiation and the other of colon carcinoma 11 years after completing therapy for SNCCL.
Survival
EFS of Patients With CNS Disease at Diagnosis by Marrow Status
EFS of Patients With CNS Disease at Diagnosis by Marrow Status and LDH Level at Diagnosis Both marrow status and LDH level at diagnosis were significant independent prognostic factors in this series. In a Cox multivariate analysis that simultaneously controlled for marrow status, CNS status, and LDH level at diagnosis, the RFR for patients with M2/M3 marrow was 1.4 (95% confidence interval [CI], 0.96 to 2.0; P = .087) (Table 5). The RFR for patients with LDH levels greater than 500 IU/mm3 was 2.2 (95% CI, 1.5 to 3.0; P < .001). The RFR for patients with CSF+/Mass disease compared with those with CNS- was 1.5 (95% CI, 0.88 to 2.6; P = .15). However, one could argue that the subset of 44 patients treated with LSA2L2 therapy on the earliest study, CCG-551, were not treated with optimal B-cell–directed therapy based on the results of the CCG-551 study itself.12 If these patients are excluded, the estimated RFR for patients with CNS disease increases from 1.5 to 1.7 and the P value associated with this RFR decreases from .15 to .08.
The presence of isolated CNPs did not confer a worse prognosis (RFR, 0.87; 95% CI, 0.36 to 2.1; P = .76) (Table 5). When CNS status was excluded from the Cox analysis, the RFR estimates for marrow status and LDH level remained essentially unchanged, although the P value for marrow status decreased to .029 (Table 6).
EFS of Patients With CSF+/Mass by CNS Irradiation The EFS ± SE for 36 CNS+ patients who received irradiation was 43% ± 9%, compared with 47% ± 12% for 13 patients who did not receive irradiation (P = .74).
Survival According to Type of Treatment
CNS involvement at diagnosis in patients with disseminated SNCCL is not uncommon and is found in 4% to 27% of cases.4-9,11,17 The variation in the reported incidence of CNS disease at presentation could be attributed to the inclusion or exclusion of patients with greater than 25% bone marrow involvement and/or patients with isolated CNPs. Our incidence of approximately 10%, with inclusion of patients with all degrees of bone marrow involvement, is in agreement with other recent multi-institutional studies.8,9 There was no clear association between sites of primary disease and CNS disease at diagnosis in our study. Involvement of the jaw, a site that is known for its association with CNS disease (particularly in patients with African Burkitt’s lymphoma), occurred in only two patients. The diagnosis of jaw involvement was by biopsy in one patient and by plain x-ray and bone scan in the other. This approach sharply contrasts with that of a previous study of patients with disseminated SNCCL with CNS involvement in which jaw involvement was noted to occur in 14 of 120 patients at diagnosis and was highly correlated with CNS disease.17 Because of the nature of dissemination, the majority of patients had involvement of multiple anatomic regions: 21 patients had head and neck primaries (11 of which were in the facial region) in addition to other sites that are close to parameningeal sites, which have a predilection for CNS spread. An additional 24 patients also had abdominal primaries. The presence of isolated CNPs in patients with disseminated SNCCL did not seem to impact on overall survival or EFS in our study, with eight of 13 patients surviving disease-free after treatment. Survival for these patients was not significantly different from that of patients without CNS disease, irrespective of marrow status. However, given the small number of patients with isolated CNPs in this study who were, by definition, suffering from CNS disease at the time of treatment and who received CNS-directed therapy, it is difficult to determine the independent impact of this factor on overall prognosis. In the study by Haddy et al,17 nine (7.5%) of 120 patients with SNCCL had isolated CNPs; five of these nine patients were long-term survivors, albeit after CNS-directed therapy. Ingram et al18 treated six patients with SNCCL (five with disseminated disease), five of whom presented with isolated CNPs at diagnosis. All patients received CNS-directed chemotherapy and radiotherapy. Two patients (both with isolated CNPs) were reported to be disease-free survivors. Inthis context, it is interesting to note that, in the BFM-86 study of SNCCL reported by Reiter et al,7 patients with isolated CNPs were not considered to have CNS disease, although in the subsequent BFM-90 study, patients who presented with isolated cranial palsies were treated as having CNS disease.9,19 Patients with CSF+/Mass in our study had a slightly inferior outcome compared with patients without CNS disease. Although more patients in the CSF+/Mass group had bone marrow involvement and elevated LDH levels at diagnosis, this analysis suggests that the presence of CSF+/Mass confers a slightly higher risk of treatment failure than does no CNS involvement, even after correcting for bone marrow status and LDH level at diagnosis. Because of the small number of patients with CNS disease in this sample and the high association of CNS status with both marrow status and LDH level, the statistical evidence for this higher risk is weak. Also, the EFS for patients with CNS disease, except for those treated on CCG-551, was uniformly greater than 55% and not significantly different, although it is possible that a small number of patients in each treatment era might have precluded meaningful statistical analysis. It must also be pointed out that five of the 27 deaths resulted from acute toxicity, which possibly reflects the intensity of treatment received by virtue of having CNS disease. Although it is possible that the improved supportive care that is available today might have spared these patients from toxicity, their possible outcome in the absence of death from toxicity remains speculative. Our results are in keeping with those of other multi-institutional studies reported recently in the literature. In the French LMB-89 protocol for childhood SNCCL, patients with CNS disease had slightly inferior EFS rates, with 79% for patients with stage IV disease with CNS disease at diagnosis and 88% for patients without CNS involvement.8 Also, in the BFM 90 study of SNCCL for children, EFS for patients with CNS disease was 72%, compared with 81% for those without CNS disease at presentation.9 Because the distribution of the types of CNS disease was not available from these studies, these comparisons have to be interpreted with caution. However, our results differ from those of a single-institution study reported by Haddy et al17 on 29 patients with CNS involvement among 120 patients treated for disseminated SNCCL. This series included patients with CNS disease at diagnosis and relapse. EFS in patients with CNS involvement did not differ from that of patients without CNS disease. Similarly, a recent Pediatric Oncol-ogy Group study of disseminated SNCLL and B-cell leukemia has demonstrated no survival difference between patients with and those without CNS disease at diagnosis.11 It is possible that treatment differences could contribute to the differences in outcome between studies. Although neuraxis irradiation was stipulated in all of the treatment protocols, some patients did not receive irradiation by physician intent. This enabled us to compare the outcome between patients who did and those who did not receive CNS radiotherapy. The use of CNS radiotherapy did not seem to impact favorably on patients with CNS disease in our study, despite the fact that most patients received the protocol-recommended doses of CNS irradiation. Because of the lack of randomization for this treatment in any of our four studies, it is possible that our data may be biased, either because of physician discretion or because patients who did receive radiotherapy were somehow worse off, and may not directly reflect on the efficacy of radiotherapy in these patients. On the other hand, the role for CNS irradiation in patients with non-Hodgkin’s lymphoma with or without CNS involvement has been questioned in previous studies.17,19,20 The recently reported results of the BFM 90 study have shown that, in patients with SNCCL and CNS involvement, triple IT therapy alone is adequate when given concomitantly with high-dose methotrexate and cytarabine.19 However, the use of triple IT chemotherapy in acute lymphoblastic leukemia has been shown to be associated with excessive neurotoxicity, even in the absence of CNS irradiation, and possibly with inferior EFS.21 In light of the results of these studies and the known neurologic sequelae associated with CNS radiotherapy, particularly when given with high-dose methotrexate, the use of IT therapy with MTX or Ara-C alone for these patients might be a safe and effective approach. Thus, in our current study of children with disseminated SNCCL (CCG-5961), we evaluated whether additional doses of high-dose intravenous MTX and IT MTX could safely replace cranial irradiation in patients with CNS disease at diagnosis.22 Although we have shown that the presence of blasts in the CSF with or without a CNS mass confers a slightly worse prognosis in patients with disseminated SNCCL, our results must be viewed in the context of the treatment available to these patients in the different time periods of this study. The treatment for SNCCL has evolved considerably in the last several years, with risk-based intensive therapy strategies improving the outcome for high-risk patients who were initially thought to be incurable. It is likely that adverse prognostic factors once thought to be important predictors of outcome might, with improvements in therapy, become obsolete in the future. The recent French and German studies have clearly demonstrated that intensive systemic and IT chemotherapy with or without CNS irradiation has dramatically improved thesurvival of these patients. Continuing refinements in therapy are required to further improve EFS and decrease treatment-related toxicities.
Supported by the Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services, Bethesda, MD.
1. Link MP, Shuster JJ, Donaldson SS, et al: Treatment of children and young adults with early-stage non-Hodgkin’s lymphoma. N Engl J Med 337:1259-1266, 1997 2. Meadows AT, Sposto R, Jenkin RDT, et al: Similar efficacy of 6 and 18 months of therapy with four drugs (COMP) for localized non-Hodgkin’s lymphoma of children: A report from the Children’sCancer Study Group. J Clin Oncol 7:92-99, 1989[Abstract] 3. Murphy SB, Bowman WP, Abromowitch M, et al: Results of treatment of advanced-stage Burkitt’s lymphoma and B cell (Sig+) acute lymphoblastic leukemia with high-dose fractionated cyclophosphamide and coordinated high-dose methotrexate and cytarabine. J Clin Oncol 4:1732-1739, 1986[Abstract] 4. Murphy SB, Fairclough DL, Hutchison RE, et al: Non-Hodgkin’s lymphoma of childhood: An analysis of the histology, staging, and response to treatment of 338 cases at a single institution. J Clin Oncol 7:186-193, 1989[Abstract]
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Bowman WP, Shuster JJ, Cook B, et al: Improved survival for children with B-cell acute lymphoblastic leukemia and stage IV small non–cleaved-cell lymphoma: A Pediatric Oncology Group study. J Clin Oncol 14:1252-1261, 1996 12. Anderson JR, Wilson JF, Jenkin RDT, et al: Childhood non-Hodgkin’s lymphoma: The results of a randomized therapeutic trialcomparing a 4-drug regimen (COMP) with a 10-drug regimen (LSA2-L2). N Engl J Med 308:559-565, 1983[Abstract] 13. Chilcote RR, Krailo M, Kjeldsberg C, et al: Daunomycin plus COMP vs COMP therapy in childhood non-lymphoblastic lymphomas. Proc Am Soc Clin Oncol 10:289a, 1991 (abstr 1011) 14. Finlay JL, Anderson JR, Cecalupo AJ, et al: Disseminated nonlymphoblastic lymphoma of childhood: A Children’s Cancer Group Study, CCG-552. Med Pediatr Oncol 23:453-463, 1994[Medline] 15. Cairo MS, Krailo M, Morse R, et al: The efficacy of two short but intensive regimens (CCG "Orange" and "French" LMB-89-C) in children with advanced non-lymphoblastic lymphoma (NLL). Proc Am Soc Clin Oncol 15:431a, 1996 (abstr 1335) 16. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958
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Haddy TB, Adde MA, Magrath IT: CNS involvement in small noncleaved-cell lymphoma: Is CNS disease per se a poor prognostic sign? J Clin Oncol 9:1973-1982, 1991 18. Ingram LC, Fairclough DL, Furman WL, et al: Cranial nerve palsy in childhood acute lymphoblastic leukemia and non-Hodgkin’s lymphoma. Cancer 67:2262-2268, 1991[Medline] 19. Jansen P, Schrappe M, Zimmermann M, et al: Intraventricularly applied chemotherapy and intensive systemic therapy is effective for CNS positive patients with Burkitt type lymphomas or acute B-cell leukemia (B-ALL). Med Pediatr Oncol 29:359, 1997 (abstr O-149) 20. Mandell LR, Wollner N, Fuks Z: Is cranial radiation necessary for CNS prophylaxis in pediatric NHL? Int J Radiat Oncol Biol Phys 13:359-363, 1987[Medline] 21. Mahoney DH Jr, Shuster JJ, Nitschke R, et al: Acute neurotoxicity in children with B-precursor acute lymphoid leukemia: An association with intermediate-dose intravenous methotrexate and intrathecal triple therapy—A Pediatric Oncology Group study. J Clin Oncol 16:1712-1722, 1998[Abstract] 22. Cairo MS, Gerrard M, Patte C: A new protocol for treatment of mature B-cell lymphoma/leukaemia (BCLL): FAB LMB 96, A SFOP LMB 96/CCG-5961/UKCCSG NHL 9600 international cooperative study. Med Pediatr Oncol 29:357, 1997 (abstr O-144) Submitted September 9, 1999; accepted January 29, 2000.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
500 IU/L suffered disease relapse, compared with three of eight patients with LDH levels of greater than 500 IU/L. In the group with CSF+/Mass, two of 13 patients with LDH 
